α-Aminoalkyl-4-hydroxy-3-alkylsulfonylmethylphenyl ketones

ABSTRACT

α-Aminoalkyl-4-hydroxy-3-alkylsulfonylmethylbenzyl alcohols having β-adrenergic stimulant activity, particularly as selected bronchodilators, are prepared from 4-hydroxyphenones by conversion to a 3-alkylsulfonylmethylphenone, bromination of these phenones and treatment of the resulting α-bromo derivatives with an N-benzyl secondary amine, followed by catalytic hydrogenation to remove the benzyl groups and reduce the ketone moiety.

This is a division of application Ser. No. 359,063, filed May 10, 1973and now U.S. Pat. No. 3,917,704, which is a continuation-in-part of Ser.No. 236,177, filed Mar. 20, 1972, now abandoned.

This invention relates to novelα-aminoalkyl-4-hydroxy-3-alkylsulfonylmethylbenzyl alcohols which haveuseful pharmacodynamic activity. More specifically, the compounds ofthis invention have utility as β-adrenergic stimulants with relativelygreater activity on respiratory smooth muscle than on cardiac muscle.Therefore these compounds have direct bronchodilator action with minimalcardiac stimulation as demonstrated in standard pharmacological testprocedures.

Two in vitro test systems used for determining selective β-stimulantactivity are: (1) effect on spontaneous tone of guinea pig trachealchain preparations as a measure of β-stimulant (direct relaxant) effecton airway smooth muscle, and (2) effect on rate of spontaneously beatingright atria of the guinea pig as a measure of β-stimulant effect oncardiac muscle. The compounds of this invention have selectivebronchodilating properties since they are active in (1) above at a doselower than is required in (2) above resulting in a positive separationratio.

The compounds of this invention are represented by the following generalstructural formula: ##STR1## in which: R represents lower alkyl of from1 to 5 carbon atoms, straight or branched chain;

R₁ represents a branched chain lower alkyl group of from 3 to 5 carbonatoms, a cycloalkyl or cycloalkylmethyl group, the cycloalkyl moietyhaving from 3 to 6 carbon atoms, or ##STR2## R₂ represents hydrogen,methyl or ethyl; and R₃ and R₄ represent hydrogen, hydroxy or methoxy;and

R₅ represents hydrogen or methyl.

Preferred compounds of this invention are represented by formula I abovewhen R is methyl; R₁ is isopropyl, t-butyl, cyclopropyl, cyclopentyl or3,4-dimethoxyphenylisopropyl; and R₂ is hydrogen.

The compounds of this invention may be used in the form of apharmaceutically accpetable acid addition salt having the utility of thefree base. Such salts, prepared by methods well known to the art, areformed with both inorganic or organic acids, for example: maleic,fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic,methansesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric,salicylic, citric, glyconic, aspartic, stearic, palmitic, itaconic,glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric,hydrobromic, sulfuric, cyclohexyl sulfamic, phosphoric and nitric acids.

Further the compounds of this invention contain at least one asymmetriccarbon atom which is resolvable into d- and l- optical isomers. When R₂in formula I is not hydrogen another asymmetric carbon atom is formedand these compounds (diastereoisomers) are designated as erythro andthreo isomers which may be resolved as d, l optical isomers. Unlessotherwise specified in the description and accompanying claims, it isintended to include all isomers, whether separated or mixtures thereof.

A preferred compound of this invention isα-(t-butylaminomethyl)-4-hydroxy-3-(methylsulfonylmethyl)benzyl alcoholwhich relaxes the spontaneous tone of guinea pig tracheal ringpreparation at an ED₅₀ of 0.0051 mcg/ml while increasing the rate ofcontraction of guinea pig right atria at an ED₂₅ or 8.28 mcg/ml. Theseactivities give an absolute separation ratio of 1,620 which is a3,340-fold improvement when compared to the corresponding activity ofd,l-isoproterenol (absolute separation ratio = 0.5) in similar in vitropreparations.

The compounds of this invention are prepared as shown in the followingsequence of reactions: ##SPC1##

in which R, R₁ and R₂ are as defined in Formula I. Thus, as shown above,a 4-hydroxyphenone is chloromethylated with formaldehyde andhydrochloric acid and is treated with the sodium or magnesium salt of analkylsulfinic acid to yield the alkylsulfonylmethyl derivative. Thelatter is brominated and the resultant α-bromophenone is reacted with anN-benzylamine to give the corresponding α-benzylaminophenone. Thisderivative is hydrogenated catalytically, preferably withpalladium-on-carbon, to give the debenzylated alkylsulfonylmethylbenzylalcohol product.

It will be appreciated that the aminoketone derivatives of formula II inthe above reaction sequence are useful intermediates and as such form apart of this invention.

The compounds of this invention may be administered orally orparenterally in conventional dosage unit forms such as tablets,capsules, injectables, aerosols, or the like, by incorporating theappropriate dose of a compound of formula I with carriers according toaccepted pharmaceutical practices.

Preferably a compound or an acid addition salt thereof is admnisteredorally to an animal organism in a tablet or capsule comprising an amountsufficient to produce β-adrenergic stimulant activity. Each dosage unitwill contain the active ingredient in an amount of about 1 mg. to about40 mg., preferably from about 3 mg. to about 20 mg. Advantageously equaldoses will be administered 2 to 4 times daily with the daily dosageregimen being about 2 mg. to about 160 mg., preferably from about 6 mg.to about 80 mg.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly the carrier or diluent can includeany time delay material well known to the art, such as glycerylmonostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be about 25 mg. to about 1 g. If a liquid carrier is used, thepreparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule, or an aqueous ornonaqueous liquid suspension.

Of particular applicability is an aerosol dispensing system wherein theactive medicament is incorporated with Freon (fluorohydrocarbon) orother inert propellant in an aerosol container. Such an aerosol systemwill deliver a metered dose of about 100 mcg. to about 650 mcg.,administered once or twice at a time as needed.

The foregoing is a general description of how to prepare the compoundsof this invention. The following examples illustrate the preparation ofspecific compounds having β-adrenergic stimulant activity. However, thisshould not be construed as a limitation of the invention sinceappropriate variations in the starting materials will produce otherproducts set forth hereinabove.

EXAMPLE 1

To a mixture of 260 cc. of 37% formaldehyde and 1800 cc. of concentratedhydrochloric acid is added 400 g. of p-hydroxyacetophenone at atemperature of about 45° C. The mixture is maintained at 50° C. for twohours, filtered, and washed with water to give3-chloromethyl-4-hydroxyacetophenone, m.p. 154° C. dec.

A mixture of 40 g. of 3-chloromethyl-4-hydroxyacetophenone and 26 g. ofmagnesium methyl sulfinate in 500 ml. of ethanol is refluxed withstirring for 3 hours. The reaction mixture is then concentrated invacuo. The resultant oil is redissolved in chloroform and washed withwater. The chloroform is dried and evaporated to give4-hydroxy-3-methylsulfonylmethylacetophenone, m.p. 206.5°-208.5°C.

A mixture of 14.0 g. of 4-hydroxy-3-methylsulfonylmethylacetophenone,9.3 g. of potassium carbonate, 7.8 ml. of benzyl chloride and acatalytic amount of sodium iodide in 250 ml. of acetone and 250 ml. ofwater is refluxed with stirring for 16 hours. The acetone is removed andthe aqueous phase is extracted with chloroform, washed with water, driedand evaporated to yield an oil which is recrystallized in isopropylalcohol to give crystalline4-benzyloxy-3-methylsulfonylmethylacetophenone, m.p. 94°-97° C.

To a stirred solution of 7.7 g. of4-benzyloxy-3-methylsulfonylmethylacetophenone and 2.15 g. of2-pyrrolidone in 300 ml. of tetrahydrofuran is added 12.5 g. ofpyrrolidone hydrotribromide (PHT) and the stirring is continued for 56hours at room temperature. The mixture is filtered and the filtrateconcentrated in vacuo to give an oil which crystallizes upon standing.The crystals are redissolved in chloroform. The chloroform solution iswashed with water, dried and concentrated to yield a solid which isrecrystallized from acetonitrile to give4-benzyloxy-α-bromo-3-methylsulfonylmethylacetophenone, m.p. 143°-144°C.The latter (100 g.) is dissolved in 1 l. of acetonitrile and 82 g. ofN-benzl-N-t-butylamine is added. The mixture is stirred and refluxed forfour hours, cooled and diluted with ether. CrystallineN-benzyl-N-t-butylamine hydrobromide is filtered. The filtrate isacidified with ethereal hydrogen chloride and ether is added to give4-benzyloxy-α(N-benzyl-N-t-butylamino)-3-(methylsulfonylmethyl)acetophenonehydrochloride, m.p. 152°-154°C.

A mixture of 20 g. of4-benzyloxy-α(N-benzyl-N-t-butylamino)-3-(methylsulfonylmethyl)acetophenonehydrochloride, 10 g. of 5% palladium-on-carbon and 125 ml. of ethanol ishydrogenated on the Parr apparatus at room temperature, using an initialhydrogen pressure of 60 psi. The reaction mixture is filtered and thefiltrate is concentrated in vacuo. The residue is crystallized withether-ethanol to yieldα-(t-butylaminomethyl)-4-hydroxy-3-(methylsulfonylmethyl)benzyl alcoholhydrochloride, m.p. 219°-220°C.

EXAMPLE 2

Similarly, refluxing a solution of 3-chloromethyl-4-hydroxyacetophenonewith sodium ethyl sulfinate or sodium butylsulfinate in ethanol andproceeding with the ensuing reactions as described above yields thecorrespondingα-(t-butylaminomethyl)-4-hydroxy-3-(ethylsulfonylmethyl)benzyl alcoholhydrochloride orα-(t-butylaminomethyl)-4-hydroxy-3-(butylsulfonylmethyl)benzyl alcoholhydrochloride. EXAMPLE 3

Employing p-hydroxypropiophenone and p-hydroxybutyrophenone as thestarting materials respectively and continuing as described in Example 1yields α-(1-t-butylaminoethyl)-4-hydroxy-3-(methanesulfonylmethyl)benzylalcohol andα-(1-t-butylaminopropyl)-4-hydroxy-3-(methylsulfonylmethyl)benzylalcohol hydrochloride.

EXAMPLE 4

Following the procedures outlined in Example 1,4-benzyloxy-α-bromo-3-methanesulfonylmethylacetophenone is condensedwith N-benzylisopropylamine. Similar hydrogenation overpalladium-on-carbon givesα-isopropylaminomethyl-4-hydroxy-3-(methylsulfonylmethyl)benzyl alcohol.

Reacting α-bromo-4-benzyloxy-3-(methylsulfonylmethyl)-acetophenone withN-benzyl-3,4-dimethoxyphenylisopropylamine followed by hydrogenationyields the productα-[2-(3,4-dimethoxyphenyl)methylethylaminomethyl]-4-hydroxy-3-(methylsulfonylmethyl)benzylalcohol.

Similarly, employing N-benzylcyclopropylmethylamine in the abovereaction followed by hydrogenation, there is obtainedα-(cyclopropylmethylaminomethyl)-4-hydroxy-3-(methylsulfonylmethyl)benzylalcohol.

Following the procedures outlined in Example 1, condensation of4-benzyloxy-α-bromo-3-methylsulfonylmethylacetophenone withN-benzylcyclopentylamine followed by hydrogenation givesα-(cyclopentylaminomethyl)-4-hydroxy-3-(methylsulfonylmethyl)benzylalcohol.

EXAMPLE 5

Following the procedures of Example 1, condensation of4-benzyloxy-α-bromo-3-methylsulfonylmethylacetophenone withN-benzylphenylisopropylamine followed by hydrogenation yieldsα-(2-phenyl-1-methylethylaminomethyl)-4-hydroxy-3-(methylsulfonylmethyl)benzylalcohol.

Similarly, reaction of the 4-benzyloxy-α-bromoacetophenone with3,4-dibenzyloxyphenylisopropylamine yields as the final productα-[(2-(3,4-dihydroxyphenyl)-1-methylethylaminomethyl]-4-hydroxy-3-(methylsulfonylmethyl)benzylalcohol.

EXAMPLE 6

Employing the procedures of Example 1,4-benzyloxy-α-bromo-3-methylsulfonylmethylacetophenone is reacted withN-benzyl-4-benzyloxyphenylisopropylamine which followed by hydrogenationgivesα-[2-(4-hydroxyphenyl)-1-methylethylaminomethyl]-4-hydroxy-3-(methylsulfonylmethyl)benzylalcohol.

EXAMPLE 7

Following the procedures outlined in Example 1,4-benzyloxy-α-bromo-3-methanesulfonylmethylacetophenone is reacted withN-benzyl-4-methoxypheny-t-butylamine which followed by hydrogenationgivesα-[2-(4-methoxyphenyl)-1,1-dimethylethylaminomethyl]-4-hydroxy-3-(methylsulfonylmethyl)-benzylalcohol.

The alcohol is treated with hydrogen chloride in methanol-ether givingα-[2-(4-methoxyphenyl)-1,1-dimethylethylaminomethyl]-4-hydroxy-3-(methylsulfonylmethyl)benzylalcohol hydrochloride as colorless crystals having a melting point of180°-182°C.

Similarly employing N-benzylcyclobutylamine in the above reactionfollowed by hydrogenation and treating the resultant alcohol withhydrogen chloride in methanol-ether yieldsα-(cyclobutylaminomethyl)-4-hydroxy-3-methylsulfonylmethyl)benzylalcohol hydrochloride having a melting point of 193°-194° C.

EXAMPLE 8

    ______________________________________                                        Ingredients            Mg./Capsule                                            ______________________________________                                        α-(t-butylaminomethyl)-4-hydroxy-                                       3-(methylsulfonylmethyl)benzyl alcohol                                                               2.242*                                                 Starch, U.S.P.         50.78                                                  Lactose, U.S.P.        142.00                                                 Magnesium Stearate, U.S.P.                                                                           3.00                                                   ______________________________________                                         *Equivalent to 2.0 mg. of free base                                      

All the ingredients are thoroughly mixed and placed in a hard gelatincapsule.

One capsule is taken three times a day.

EXAMPLE 9 Aerosol Spray

    ______________________________________                                        Ingredients            Mg./Spray                                              ______________________________________                                        α-(t-butylaminomethyl)-4-hydroxy-                                       3-(methylsulfonylmethyl)benzyl alcohol                                                                0.3363*                                               Sorbitan Trioleate      0.3000                                                Freon 11 (Trichloromonofluoromethane,                                         N.F.)                  10.0000                                                Freon 12 (Dichlorodifluoromethane, N.F.)                                                             14.8000                                                Freon 114 (Dichlorotetrafluoromethane,                                        N.F.)                  12.2000                                                ______________________________________                                         *Equivalent to 300 mcg. free base/spray                                  

The above ingredients are placed in an aerosol spray dispensing systemand result in the above indicated dose per spray.

What is claimed is:
 1. A chemical compound of the formula: ##EQU1## wherein: R is straight or branched chain lower alkyl of from 1 to 5 carbon atoms;R₁ is branched chain lower alkyl of from 3 to 5 carbon atoms, cycloalkyl or cycloalkylmethyl, the cycloalkyl moiety having from 3 to 6 carbon atoms, or ##EQU2## R₂ is hydrogen, methyl or ethyl; R₃ and R₄ are hydrogen, hydroxy or methoxy, and R₅ is hydrogen or methyl.
 2. A chemical compound according to claim 1 in which R is methyl.
 3. A chemical compound according to claim 2 in which R₂ is hydrogen.
 4. A chemical compound according to claim 3 in which R₁ is t-butyl.
 5. A chemical compound according to claim 3 in which R₁ is cyclopentyl.
 6. A chemical compound according to claim 1 in which R is ethyl and R₂ is hydrogen.
 7. A chemical compound according to claim 2 in which R₁ is isopropyl and R₂ is hydrogen.
 8. A chemical compound according to claim 2 in which R₂ is methyl or ethyl.
 9. A chemical compound according to claim 8 in which R₂ is ethyl and R₁ is t-butyl.
 10. A chemical compound according to claim 8 in which R₂ is methyl and R₁ is tertiary butyl. 